Pulse dosing regimen and methods of treatment

ABSTRACT

A novel dosing regimen for erlotinib or a pharmaceutically acceptable salt thereof is described herein. The dosing regimen demonstrates impressive control of central nervous system disease, which is better than that reported with standard dose erlotinib. The use of the novel dosing regimen for treating patients in need thereof, including for controlling formation of metastatic brain, leptomeninges, or CNS lesions in a patient with non-small cell lung cancer (NSCLC) that harbors epidermal growth factor receptor (EGFR) mutation with or without pre-existing brain metastases, is also described herein.

FIELD OF THE INVENTION

The present disclosure describes a novel dosing regimen for erlotinib ora pharmaceutically acceptable salt thereof. The dosing regimendemonstrates impressive control of central nervous system disease, whichis better than that reported with standard dose erlotinib. The presentdisclosure describes the use of the novel dosing regimen for treatingpatients in need thereof, including for controlling formation ofmetastatic brain, leptomeninges, or CNS lesions in a patient withnon-small cell lung cancer (NSCLC) that harbors epidermal growth factorreceptor (EGFR) mutation with or without pre-existing brain,leptomeninges, or CNS metastases.

BACKGROUND OF THE INVENTION

TARCEVA® (erlotinib HCI) is a tyrosine kinase inhibitor (TKI). Asreferenced in the FDA-approved label, TARCEVA® is indicated in theUnited States for first-line treatment of patients with metastaticnon-small cell lung cancer (NSCLC) whose tumors have epidermal growthfactor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitutionmutations as detected by an FDA-approved test; maintenance treatment ofpatients with locally advanced or metastatic NSCLC whose disease has notprogressed after four cycles of platinum based first-line chemotherapy;treatment of locally advanced or metastatic NSCLC after failure of atleast one prior chemotherapy regimen; and first-line treatment ofpatients with locally advanced, unresectable or metastatic pancreaticcancer, in combination with gemcitabine.

TARCEVA® (erlotinib), a tyrosine kinase inhibitor, is a quinazolinaminewith the chemical nameN-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine. TARCEVA®contains erlotinib as the hydrochloride salt that has the followingstructural formula:

Reference is made to U.S. RE 41,065, herein incorporated by referencewith regard to the description and synthesis of the compound.

Erlotinib hydrochloride has the molecular formula C₂₂H₂₃N₃O₄.HCl and amolecular weight of 429.90. The molecule has a pKa of 5.42 at 25° C.Erlotinib hydrochloride is very slightly soluble in water, slightlysoluble in methanol and practically insoluble in acetonitrile, acetone,ethyl acetate, and hexane. Aqueous solubility of erlotinib hydrochlorideis dependent on pH with increased solubility at a pH of less than 5 dueto protonation of the secondary amine. Over the pH range of 1.4 to 9.6,maximal solubility of approximately 0.4 mg/mL occurs at a pH ofapproximately 2.

Epidermal growth factor receptor (EGFR) is expressed on the cell surfaceof both normal and cancer cells. In some tumor cells signaling throughthis receptor plays a role in tumor cell survival and proliferationirrespective of EGFR mutation status. Erlotinib reversibly inhibits thekinase activity of EGFR, preventing autophosphorylation of tyrosineresidues associated with the receptor and thereby inhibiting furtherdownstream signaling. Erlotinib binding affinity for EGFR exon 19deletion or exon 21 (L858R) mutations is higher than its affinity forthe wild type receptor. Erlotinib inhibition of other tyrosine kinasereceptors has not been fully characterized.

As with other ATP competitive small molecule tyrosine kinase inhibitors,patients may develop resistance. Over 50% of resistance is caused by amutation in the ATP binding pocket of the EGFR kinase domain involvingsubstitution of a small polar threonine residue with a large nonpolarmethionine residue, T790M. See, Balak et al., Novel D761Y and commonsecondary T790M mutations in epidermal growth factor receptor-mutantlung adenocarcinomas with acquired resistance to kinase inhibitors,Clin. Cancer Res 12 (1): 6494-501, (2006). While proponents of the‘gatekeeper’ mutation hypothesis suggest this mutation prevents thebinding of erlotinib through steric hindrance, research suggests thatT790M confers an increase in ATP binding affinity, thereby reducing theinhibitory efficacy of erlotinib. See, Yun et al., The T790M mutation inEGFR kinase causes drug resistance by increasing the affinity for ATP,PNAS 105 (6): 2070-5, (2008).

EGFR-mutant lung cancers are highly responsive to EGFR tyrosine kinaseinhibitors (TKIs) with superior progression free survival when comparedto cytotoxic chemotherapy. See, for example, Lee et al., Impact ofSpecific Epidermal Growth Factor Receptor (EGFR)Mutations and ClinicalCharacteristics on Outcomes after Treatment with EGFR Tyrosine KinaseInhibitors Versus Chemotherapy in EGFR-Mutant Lung Cancer: AMeta-Analysis, Journal of clinical oncology. 2015; 33(17):1958-65; Moket al., Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma,The New England Journal of Medicine, 2009; 361(10):947-57; Rosell etal., Erlotinib versus standard chemotherapy as first-line treatment forEuropean patients with advanced EGFR mutation-positive non-small-celllung cancer (EURTAC): a multicentre, open-label, randomised phase3trial, The Lancet Oncology, 2012; 13(3):239-46; and Sequist et al.,Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in PatientsWith Metastatic Lung Adenocarcinoma With EGFR Mutations, Journal ofClinical Oncology, 2013; 31(27):3327-34. The majority of patients willrespond to erlotinib, gefitinib, and afatinib, but in less than a yeardevelop resistance to further therapy with these agents. See, Sequist etal., Phase III Study of Afatinib or Cisplatin Plus Pemetrexed inPatients With Metastatic Lung Adenocarcinoma With EGFR Mutations,Journal of Clinical Oncology. 2013; 31(27):3327-34; Maemondo et al.,Gefitinib or chemotherapy for non-small-cell lung cancer with mutatedEGFR, The New England Journal of Medicine, 2010; 362(25):2380-8; Mok etal., Gefitinib or Carboplatin-Paclitaxel in Pulmonary Adenocarcinoma. N.Engl. J. Med., 2009; 361(10):947-57; and Janne et al., Randomized PhaseII Trial of Erlotinib Alone or With Carboplatin and Paclitaxel inPatients Who Were Never or Light Former Smokers With Advanced LungAdenocarcinoma: CALGB 30406Trial, Journal of Clinical Oncology, 2012;39(17): 2063-9. As noted hereinabove, the most common mechanism ofresistance is acquisition of an EGFR T790M mutation, identified in 60%of patients with acquired resistance to EGFR TKIs. See also, Kobayashiet al., EGFR mutation and resistance of non-small-cell lung cancer togefitinib, The New England Journal of Medicine. 2005; 352(8):786-92, andYu et al., Analysis of tumor specimens at the time of acquiredresistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lungcancers, Clinical Cancer Research, 2013, 19(8):2240-7. Acquiredresistance occurs, however, with the central nervous system as afrequent site of relapse. A parallel strategy to improve outcomes inpatients with EGFR-mutant lung cancers is to adjust initial treatment todelay or prevent acquired resistance. While some have investigated EGFRTKIs in combination with other agents, modulating EGFR TKI dosing toprevent resistance in patients with EGFR-mutant lung cancers has notbeen assessed. See, Johnson et al., Phase I/II Study of HSP90InhibitorAUY922 and Erlotinib for EGFR-Mutant Lung Cancer With AcquiredResistance to 18 Epidermal Growth Factor Receptor Tyrosine KinaseInhibitors, Journal of Clinical Oncology, 2015, 33(15):1666-73, Riely etal., Prospective assessment of discontinuation and reinitiation oferlotinib or gefitinib in patients with acquired resistance to erlotinibor gefitinib followed by the addition of everolimus, Clinical CancerResearch, 2007, 13(17):5150-5, Reguart et al., Phase I/II trial ofvorinostat (SAHA) and erlotinib for non-small cell lung cancer (NSCLC)patients with epidermal growth factor receptor (EGFR) mutations aftererlotinib progression, Lung Cancer, 2014, 84(2):161-7, Johnson et al.,Phase II trial of dasatinib for patients with acquired resistance totreatment with the epidermal growth factor receptor tyrosine kinaseinhibitors erlotinib or gefitinib, Journal of Thoracic Oncology. 2011,6(6):1128-31, and Goldberg et al., A phase I study of erlotinib andhydroxychloroquine in advanced non-small-cell lung cancer, Journal ofThoracic Oncology, 2012, 7(10):1602-8. Third generation EGFR TKIs, suchas osimertinib, which inhibit EGFR T790M may be effective at the time ofprogression on erlotinib, afatinib, or gefitinib.

Erlotinib was initially developed to inhibit wild-type EGFR. The 150 mgdaily dose was the maximum tolerated dose established via a phase Istudy (Hildalgo et al.), which predated knowledge of EGFR mutation. Thechoice of a 150 mg daily dose, therefore, did not take intoconsideration the development of drug resistance in patients whosetumors harbor EGFR mutations. Hidalgo et al., Phase I and pharmacologicstudy of OSI-774, an epidermal growth factor receptor tyrosine kinaseinhibitor in patients with advanced solid malignancies, Journal ofClinical Oncology, 2001, 19(13):3267-79. Mathematical modeling canpredict the evolutionary dynamics that result in proliferation ofresistant clones, and suggest potential alternative dosing schedules todelay resistance. See, Chmielecki et al., Optimization of dosing forEGFR-mutant non-small cell lung cancer with evolutionary cancermodeling, Science Translational Medicine, 2011, 3(90):90ra59, and Foo etal., Evolution of resistance to targeted anti-cancer therapies duringcontinuous and pulsed administration strategies, PLoS ComputationalBiology, 2009, 5(11):e1000557. Yu et al., used these methods to evaluatedifferent dosing schedules of erlotinib and selected twice weekly highdose of erlotinib plus daily low dose erlotinib as better able to delayprogression in the setting of pre-existing resistant, EGFR T790Mpositive cells. The mathematical prediction and hypotheses wereconfirmed in pre-clinical studies using 20 μM erlotinib/1 μM erlotiniband 100 nM afatinib/1 μM erlotinib doses. See, Chmielecki et al.,Optimization of dosing for EGFR-mutant non-small cell lung cancer withevolutionary cancer modeling, Science Translational Medicine, 2011,3(90):90ra59.

Milton et al., conducted a study of weekly high dose erlotinib inunselected patients with advanced lung cancers. See, Milton et al.,Weekly high-dose erlotinib in patients with non-small cell lung cancer(NSCLC): a phase I/II study, Cancer, 2006; 107(5):1034-41. The maximumtolerated dose (MTD) was not reached at erlotinib 2000 mg once weekly. Aseparate Phase 1 study of twice-weekly pulse dose erlotinib identifiedthe MTD to be erlotinib 1000 mg twice-weekly, with a DLT of rash seen athigher dose levels. See, Chia et al., A Phase 1 dose escalationpharmacokinetic (PK) and pharmacodynamic (PD) study of weekly and twiceweekly erltoinib in advanced stage malignancies, Journal of ClinicalOncology, 2007:25, Suppl; Abstract 3594.

Due to a wide inter-subject variability in bioavailability, lower dailydoses of erlotinib may be effective with significantly less toxicity,although not proven in a randomized trial setting. Yamada et al., Aprospective, multicentre phase II trial of low-dose erlotinib innon-small cell lung cancer patients with EGFR mutations pretreated withchemotherapy: Thoracic Oncology Research Group 0911, Eur J Cancer, 2015September; 51(14): 1904-10; Erlotinib ata dose of 25mg daily fornon-small cell lung cancers with EGFR mutations, Journal of ThoracicOncology, 2010; 5(7):1048-53; and Satoh et al., Low-dose gefitinibtreatment for patients with advanced non-small cell lung cancerharboring sensitive epidermal growth factor receptor mutations. Journalof Thoracic Oncology, 2011; 6(8):1413-7.

The available data suggest that EGFR TKI high pulse dosing is tolerableand low daily dosing is effective but these have not previously beenadministered together in patients.

Central nervous system (CNS) involvement is a major issue for patientswith EGFR-mutant lung cancers, with up to sixty percent of thesepatients developing brain or leptomeningeal metastases during theirdisease course. See, Heon et al., The impact of initial gefitinib orerlotinib versus chemotherapy on central nervous system progression inadvanced non-small cell lung cancer with EGFR mutations, Clinical CancerResearch, 2012; 18(16):4406-14; and Omuro et al., High incidence ofdisease recurrence in the brain and leptomeninges in patients withnon-small cell lung carcinoma after response to gefitinib, Cancer, 2005,103(11):2344-8. Although benefit is commonly seen with EGFR TKIs whenCNS disease is already present, these medications inconsistently lead todurable CNS control and do not prevent the emergence of CNS metastases.Up to 33% of patients with EGFR-mutant lung cancers have CNS progressionduring initial EGFR TKI therapy and in a significant subset of patients,the CNS progression occurs in the setting of continued systemic control.See, Heon et al., The impact of initial gefitinib or erlotinib versuschemotherapy on central nervous system progression in advanced non-smallcell lung cancer with EGFR mutations, Clinical Cancer Research, 2012,18(16):4406-14; Omuro et al., High incidence of disease recurrence inthe brain and leptomeninges in patients with nonsmall cell lungcarcinoma after response to gefitinib Cancer, 2005; 103(11):2344-8; andLee et al., Frequent central nervous system failure after clinicalbenefit with epidermal growth factor receptor tyrosine kinase inhibitorsin Korean patients with nonsmall-cell lung cancer, Cancer, 2010,116(5):1336-43. Central nervous system-only progression may be a resultof inadequate brain penetration, with cerebrospinal fluid (CSF)concentrations of erlotinib only 3-5% of those in plasma. See, Togashiet al., Cerebrospinal fluid concentration of erlotinib and its activemetabolite OSI-420 in patients with central nervous system metastases ofnon-small cell lung cancer, Journal of Thoracic Oncology, 2010,5(7):950-5.

SUMMARY OF THE INVENTION

Consequently, the CNS becomes a common sanctuary site of diseaseprogression due to inadequate drug delivery, not acquired drugresistance. The present inventors demonstrate that pulse dose erlotinibor a pharmaceutically acceptable salt thereof produces higher CSFconcentrations and appears effective in the treatment of CNS metastases.

Wth erlotinib 1500 mg once weekly, a peak plasma concentration of 11,300nM was reached with a concurrent CSF concentration of 120 nM which isabove the IC₅₀ of erlotinib. See, Clarke et al., High dose weeklyerlotinib achieves therapeutic concentrations in CSF and is effective inleptomeningeal metastases from epidermal growth factor receptor mutantlung cancer, Journal of Neuro-Oncology, 2010, 99(2):283-6. In an earlierseries, patients with EGFR-mutant lung cancers with CNS involvement weretreated with a median dose of erlotinib 1500 mg once weekly. Six of ninehad a partial response in the CNS. See, Grommes et al., “Pulsatile”high-dose weekly erlotinib for CNS metastases from EGFR mutant non-smallcell lung cancer, Neuro-Oncology, 2011, 13(12):1364-9.

One embodiment of the present disclosure includes a dosing regimencomprising: (i) orally administering one or more daily low dose oferlotinib or a pharmaceutically acceptable salt thereof; and (ii) orallyadministering one or more weekly high dose of erlotinib or apharmaceutically acceptable salt thereof. One aspect of the embodimentincludes a low dose of 50 mg of erlotinib or a pharmaceuticallyacceptable salt thereof. One aspect of the embodiment includes a highdose from about 600 mg to about 1350 mg of erlotinib or apharmaceutically acceptable salt thereof. One aspect of the embodimentincludes a high dose of 1200 mg of erlotinib or a pharmaceuticallyacceptable salt thereof. One aspect of the embodiment includes whereinthe daily dose is once daily. One aspect of the embodiment includeswherein the weekly dose is once or twice weekly. One aspect of theembodiment includes wherein the regimen improves tolerability over astandard 100 mg to 150 mg daily dose of erlotinib or a pharmaceuticallyacceptable salt thereof. One aspect of the embodiment includes whereinthe improved tolerability is manifested by a lower incidence in one ormore of rash, diarrhea, nausea, fatigue, or mucositis.

One embodiment of the present disclosure includes a weekly dosingregimen comprising: (i) orally administering one or more pulse dose oferlotinib or a pharmaceutically acceptable salt thereof; and (ii) orallyadministering one or more daily dose of erlotinib or a pharmaceuticallyacceptable salt thereof. One aspect of the embodiment includes whereinthe pulse dose is administered once daily on each of days 1 and 2 of aweekly dosing schedule. One aspect of the embodiment includes whereinthe daily dose is administered once daily on each of days 3 to 7 of aweekly dosing schedule. One aspect of the embodiment includes whereinthe pulse dose is from about 600 mg to about 1350 mg of erlotinib or apharmaceutically acceptable salt thereof. One aspect of the embodimentincludes wherein the pulse dose is 1200 mg erlotinib or apharmaceutically acceptable salt thereof. One aspect of the embodimentincludes wherein the daily dose is from about 25 mg to about 50 mg oferlotinib or a pharmaceutically acceptable salt thereof. One aspect ofthe embodiment includes wherein the daily dose is 50 mg erlotinib or apharmaceutically acceptable salt thereof.

One embodiment of the present disclosure includes a dosing regimen oferlotinib or a pharmaceutically acceptable salt thereof comprising: (i)administering to a patient in need thereof erlotinib or apharmaceutically acceptable salt thereof in amounts that provide asteady state concentration (C_(trough)) 0.05-10 μM in the patient; and(ii) administering to a patient in need thereof erlotinib or apharmaceutically acceptable salt thereof in amounts that provide apulsed concentration (C_(max)) of 5-50 μM in the patient. One aspect ofthe embodiment includes wherein the steady state concentration(C_(trough)) is approximately 0.5 μM. One aspect of the embodimentincludes wherein the pulsed concentration (C_(max)) is approximately 20μM. One aspect of the embodiment includes wherein the pulsedconcentration is maintained for 4 hours.

One embodiment of the present invention includes a method of treating orpreventing central nervous system (CNS) metastases in a patient in needthereof comprising: (i) orally administering one or more pulse dose oferlotinib or a pharmaceutically acceptable salt thereof; and (ii) orallyadministering one or more daily dose of erlotinib or a pharmaceuticallyacceptable salt thereof. One aspect of the embodiment includes whereinthe CNS metastases is leptomeningeal carcinomatosis. One aspect of theembodiment includes wherein the patient has extra-cranial metastaticnon-small cell lung cancer. One aspect of the embodiment includeswherein the pulse dose is administered once daily on each of days 1 and2 of a weekly dosing schedule. One aspect of the embodiment includeswherein the daily dose is administered once daily on each of days 3 to 7of a weekly dosing schedule. One aspect of the embodiment includeswherein the pulse dose is from about 600 mg to about 1350 mg oferlotinib or a pharmaceutically acceptable salt thereof. One aspect ofthe embodiment includes wherein the pulse dose is 1200 mg erlotinib or apharmaceutically acceptable salt thereof. One aspect of the embodimentincludes wherein the daily dose is from about 25 mg to about 50 mg oferlotinib or a pharmaceutically acceptable salt thereof. One aspect ofthe embodiment includes wherein the daily dose is 50 mg erlotinib or apharmaceutically acceptable salt thereof. One aspect of the embodimentincludes wherein the patient with or without pre-existing brain,leptomeninges, or CNS metastases has no progression. One aspect of theembodiment includes wherein the patient's cerebrospinal fluid (CSF) iscleared of malignant cells. One aspect of the embodiment includeswherein the patient achieves a clinical benefit. One aspect of theembodiment includes wherein the clinical benefit is one or more ofdecrease in tumor size, suppression of tumor growth, delayed time toprogression in CNS, unobservable increase in size of brain,leptomeninges, or CNS metastases or lesions, unobservable new brain,leptomeninges, or CNS metastases or lesion, delay in time from surgeryto recurrence, increase in treatment options, delay or decrease inleptomeningeal seeding in the CSF, or an ability to delay whole brainradiation.

One embodiment of the present disclosure includes a method forcontrolling formation of metastatic brain, leptomeninges, or CNS lesionsin a patient with non-small cell lung cancer (NSCLC) that harborsepidermal growth factor receptor (EGFR) mutation with or withoutpre-existing brain, leptomeninges, or CNS metastases comprising: (i)orally administering one or more pulse dose of erlotinib or apharmaceutically acceptable salt thereof; and (ii) orally administeringone or more daily dose of erlotinib or a pharmaceutically acceptablesalt thereof. One aspect of the embodiment includes wherein the pulsedose is administered once daily on each of days 1 and 2 of a weeklydosing schedule. One aspect of the embodiment includes wherein the dailydose is administered once daily on each of days 3 to 7 of a weeklydosing schedule. One aspect of the embodiment includes wherein the pulsedose is from about 600 mg to about 1350 mg of erlotinib or apharmaceutically acceptable salt thereof. One aspect of the embodimentincludes wherein the pulse dose is 1200 mg erlotinib or apharmaceutically acceptable salt thereof. One aspect of the embodimentincludes wherein the daily dose is from about 25 mg to about 50 mg oferlotinib or a pharmaceutically acceptable salt thereof. One aspect ofthe embodiment includes wherein the daily dose is 50 mg erlotinib or apharmaceutically acceptable salt thereof. One aspect of the embodimentincludes wherein the patient experiences no tumor formation in thecentral nervous system. One aspect of the embodiment includes whereinthe patient's cerebrospinal fluid is cleared of malignant cells. Oneaspect of the embodiment includes wherein the patient achieves anobjective or complete response or disease control. One aspect of theembodiment includes wherein the control is durable.

One embodiment of the present disclosure includes a combinationcomprising: (a) erlotinib or a pharmaceutically acceptable salt thereof(i) orally administered in one or more pulse dose of erlotinib or apharmaceutically acceptable salt thereof; and (ii) orally administeredin one or more daily dose of erlotinib or a pharmaceutically acceptablesalt thereof; and (b) one or more therapeutic compounds administered inan effective amount thereof. One aspect of the embodiment includeswherein the one or more therapeutic compounds are one or more oncologytherapeutic compounds. One aspect of the embodiment includes wherein theone or more therapeutic compounds are one or more inhibitors ofepidermal growth factor receptor (EGFR). One aspect of the embodimentincludes wherein the one or more therapeutic compounds are one or moreinhibitors of EGFR is a mutant-selective inhibitor of EGFR. One aspectof the embodiment includes wherein the one or more therapeutic compoundsare selected from one or more of rociletinib (CO-1686), osimertinib(AZD9291), HM61713, BI 1482694, or other third or later generation EGFRTKI. One aspect of the embodiment includes wherein the pulse dose oferlotinib or a pharmaceutically acceptable salt thereof is administeredonce daily on each of days 1 and 2 of a weekly dosing schedule. Oneaspect of the embodiment includes wherein the daily dose of erlotinib ora pharmaceutically acceptable salt thereof is administered once daily oneach of days 3 to 7 of a weekly dosing schedule. One aspect of theembodiment includes wherein the pulse dose is from about 600 mg to about1350 mg of erlotinib or a pharmaceutically acceptable salt thereof. Oneaspect of the embodiment includes wherein the pulse dose is 1200 mgerlotinib or a pharmaceutically acceptable salt thereof. One aspect ofthe embodiment includes wherein the daily dose is from about 25 mg toabout 50 mg of erlotinib or a pharmaceutically acceptable salt thereof.One aspect of the embodiment includes wherein the daily dose is 50 mgerlotinib or a pharmaceutically acceptable salt thereof. One aspect ofthe embodiment includes wherein each dose is selected from a solid orliquid form. One aspect of the embodiment includes wherein a solid formcomprises one or more of erlotinib or the one or more therapeuticcompounds complexed with a cyclodextrin and nano-encapsulated into apharmaceutically acceptable carrier.

One embodiment of the present disclosure includes a unit dose oferlotinib or a pharmaceutically acceptable salt thereof, comprising apharmaceutical composition comprising erotinib or a pharmaceuticallyacceptable salt thereof which achieves a peak concentration (C_(max)) of5-50 μM in a patient. One aspect of the embodiment includes wherein theunit dose is from about 600 mg to about 1350 mg of erlotinib or apharmaceutically acceptable salt thereof. One aspect of the embodimentincludes wherein the unit dose is about 1200 mg erlotinib or apharmaceutically acceptable salt thereof. One aspect of the embodimentincludes wherein the peak concentration (C_(max)) is approximately 20μM. One aspect of the embodiment includes wherein the peak concentrationis maintained for 4 hours. One aspect of the embodiment includes whereinthe dose is selected from a solid or liquid form. One aspect of theembodiment wherein the solid form comprises erlotinib complexed with acyclodextrin and nano-encapsulated into a pharmaceutically acceptablecarrier.

One embodiment of the present disclosure includes a method of treatingbrain, leptomeninges, or CNS metastases in a patient diagnosed withEGFR-mutant lung cancer comprising: (i) orally administering one or morepulse dose of erlotinib or a pharmaceutically acceptable salt thereof;and (ii) orally administering one or more daily dose of erlotinib or apharmaceutically acceptable salt thereof. One aspect of the embodimentincludes wherein erlotinib or a pharmaceutically acceptable salt thereofis administered once daily on each of days 1 and 2 of a weekly dosingschedule. One aspect of the embodiment includes wherein the daily doseof erlotinib or a pharmaceutically acceptable salt thereof isadministered once daily on each of days 3 to 7 of a weekly dosingschedule. One aspect of the embodiment includes wherein the pulse doseis from about 600 mg to about 1350 mg of erlotinib or a pharmaceuticallyacceptable salt thereof. One aspect of the embodiment includes whereinthe pulse dose is 1200 mg erlotinib or a pharmaceutically acceptablesalt thereof. One aspect of the embodiment includes wherein the dailydose is from about 25 mg to about 50 mg of erlotinib or apharmaceutically acceptable salt thereof. One aspect of the embodimentincludes wherein the daily dose is 50 mg erlotinib or a pharmaceuticallyacceptable salt thereof.

One embodiment includes a method of treating a patient diagnosed withgliablastoma comprising: orally administering one or more pulse dose oferlotinib or a pharmaceutically acceptable salt thereof; and orallyadministering one or more daily dose of erlotinib or a pharmaceuticallyacceptable salt thereof. In one aspect, the method includes wherein thepulse dose of erlotinib or a pharmaceutically acceptable salt thereof isadministered once daily on each of days 1 and 2 of a weekly dosingschedule. In one aspect, the method includes wherein the daily dose oferlotinib or a pharmaceutically acceptable salt thereof is administeredonce daily on each of days 3 to 7 of a weekly dosing schedule. In oneaspect, the method includes wherein the pulse dose is from about 600 mgto about 1350 mg of erlotinib or a pharmaceutically acceptable saltthereof. In one aspect, the method includes wherein the pulse dose is1200 mg erlotinib or a pharmaceutically acceptable salt thereof. In oneaspect, the method includes wherein the daily dose is from about 25 mgto about 50 mg of erlotinib or a pharmaceutically acceptable saltthereof. In one aspect, the method includes wherein the daily dose is 50mg erlotinib or a pharmaceutically acceptable salt thereof.

Glioblastoma multiforme (GBM) is the most common brain tumour and hasthe worst prognosis. Epidermal growth factor receptor (EGFR) geneamplification, mutation and re-arragement (all of which enhance tumorgrowth, survival, progression, and resistance to therapy) are frequentlyobserved in primary GBM. The most common EGFR variant in GBM, theEGFRvIll, is characterized by a deletion of 267 amino acids in theextracellular domain, leading to a receptor which is unable to bindligand yet is constitutively active. Epidermal growth factor receptor(EGFR) and EGFRvIll analysis is of current interest in glioblastoma.See, e.g., Gan et al., The Epidermal Growth Factor Receptor Variant III(EGFRvIll): Where the Wild Things are Altered, FEBS J, 2013 November,280(21): 5350-70; Gan et al., The EGFRvIll Variant in GlioblastomaMultiforme, J. Clin. Neurosci., 2009 June, 16(6): 748-54; Padfield etal., Current Therapeutics Advances Targeting EGFR and EGFRvIll inGlioblastoma, Front. Oncol., v. 5, published online 2015 January 29; andIwata et al., Inhibition of mutant EGFRvIll transformed cells bytyrosine kinase inhibitor OSI-774 (Tarceva) [Abstract No. 79]. Proc.ASCO2002; 21.

The scope of the present invention includes all combinations of aspectsand embodiments.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates a synthetic scheme for the manufacture of erlotinib.

FIG. 2 is a graphical representation of best response of target lesions(RECIST 1.1) in all patients with a radiographic assessment of response.

FIG. 3 is a graphical representation of progression-free survivalprobability from months since start of therapy.

FIG. 4 is an example of CNS response in a patient with untreated brainmetastases on the regimen, namely pulse-continuous erlotinib or apharmaceutically acceptable salt thereof.

FIG. 5 is a graphical representation of plasma concentration curves forerlotinib after multiple dosing. Blood samples were collected duringcycle 1 week 1 day 1 at 0.5, 1, 2, 4, and 6 hours after the first dose;before and four hours after erlotinib dosing on cycle 1 week 2 day 1 andcycle 1 week 4 day 1.

DETAILED DESCRIPTION

The following definitions are meant to clarify, but not limit, the termsdefined. If a particular term used herein is not specifically defined,such term should not be considered indefinite. Rather, terms are usedwithin their accepted meanings.

As referenced herein, one embodiment of the present disclosure includesa dosing regimen comprising: (i) orally administering one or more dailylow dose of erlotinib or a pharmaceutically acceptable salt thereof; and(ii) orally administering one or more weekly high dose of erlotinib or apharmaceutically acceptable salt thereof. As used herein, the terms “lowdose” and “high dose” are used relative to the other as well as relativeto a standard 100 mg to 150 mg daily dose of erlotinib or apharmaceutically acceptable salt thereof. A low dose is lower than eachof the standard dose and the high dose. Likewise, a high dose is higherthan each of the standard dose and the low dose. One aspect of theembodiment includes a low dose of 50 mg of erlotinib or apharmaceutically acceptable salt thereof. One aspect of the embodimentincludes a high dose from about 600 mg to about 1350 mg of erlotinib ora pharmaceutically acceptable salt thereof. One aspect of the embodimentincludes a high dose of 1200 mg of erlotinib or a pharmaceuticallyacceptable salt thereof.

As referenced herein, one embodiment of the present disclosure includesa weekly dosing regimen comprising: (i) orally administering one or morepulse dose of erlotinib or a pharmaceutically acceptable salt thereof;and (ii) orally administering one or more daily dose of erlotinib or apharmaceutically acceptable salt thereof. As used herein, the term“pulse dose” refers to a higher dose of erlotinib or a pharmaceuticallyacceptable salt thereof as compared to the daily dose. The term “pulsedose,” as used herein may be determined by determining a dose thatprovides higher CSF concentrations than a standard 100 mg to 150 mgdaily dose of erlotinib or a pharmaceutically acceptable salt thereof.One aspect of the embodiment includes wherein the pulse dose is fromabout 600 mg to about 1350 mg of erlotinib or a pharmaceuticallyacceptable salt thereof. One aspect of the embodiment includes whereinthe pulse dose is 1200 mg erlotinib or a pharmaceutically acceptablesalt thereof.

As used herein, the term “unit dose” refers to a dose of medicine in anindividual packet for convenience, safety, or monitoring.

As used herein, the term “tolerability” refers to the degree to whichovert adverse effects of a drug can be tolerated by a patient.Tolerability of a particular drug can be discussed in a general sense,or it can be a quantifiable measurement as part of a clinical study. Asone measure, tolerability may be determined by the rate of dropouts, orpatients that forfeit participation in a clinical study due to one ormore adverse effects.

As used herein, the term “pharmaceutically acceptable” refers tocarrier(s), diluent(s), excipient(s) or salt forms of the compounds ofthe present invention that are compatible with the other ingredients ofthe formulation and not deleterious to the recipient of thepharmaceutical composition.

As used herein, the terms “effective amount”, “therapeutic amount”, and“effective dose” refer to an amount of the compound of the presentinvention sufficient to elicit a desired pharmacological or therapeuticeffect. Moreover, the therapeutic amount of effective amount may thusresult in an effective treatment of a disorder.

Treatment of a disorder may be manifested by delaying or preventing theonset or progression of the disorder, as well as the onset orprogression of symptoms associated with the disorder. Treatment of adisorder may also be manifested by a decrease or elimination ofsymptoms, reversal of the progression of the disorder, as well as anyother contribution to the well-being of the patient.

Erlotinib may exist in free form or, where appropriate, as apharmaceutically acceptable derivative thereof. According to theinvention, a pharmaceutically acceptable derivative includes, but is notlimited to, pharmaceutically acceptable salts, esters, salts of suchesters, or any other adduct or derivative which upon administration to asubject in need is capable of providing, directly or indirectly, acompound as otherwise described herein, or a metabolite or residuethereof.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. A“pharmaceutically acceptable salt” means any non-toxic salt or salt ofan ester of a compound of this invention that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention or an active metabolite or residue thereof.As used herein, the term “active metabolite or residue thereof” meansthat a metabolite or residue thereof is also an EGFR TKI.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge, et al., describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts include thosederived from suitable inorganic and organic acids and bases. Examples ofpharmaceutically acceptable, nontoxic acid addition salts are salts ofan amino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, oxalic acid, maleic acid,tartaric acid, citric acid, succinic acid or malonic acid or by usingother methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. This inventionalso envisions the quaternization of any basic nitrogen-containinggroups of the compounds disclosed herein. Water or oil-soluble ordispersable products may be obtained by such quaternization.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounter-ions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, lower alkyl sulfonate and aryl sulfonate.

Polymorphism, the occurrence of different crystal forms, is a propertyof some molecules and molecular complexes. A single molecule, likeerlotinib, may give rise to a variety of crystalline forms havingdistinct crystal structures and physical properties like melting point,x-ray diffraction pattern, infrared absorption fingerprint, and solidstate NMR spectrum. One crystalline form may give rise to thermalbehavior different from that of another crystalline form. Thermalbehavior can be measured in the laboratory by such techniques ascapillary melting point, thermogravimetric analysis (“TGA”), anddifferential scanning calorimetry (“DSC”), which have been used todistinguish polymorphic forms. The difference in the physical propertiesof different crystalline forms results from the orientation andintermolecular interactions of adjacent molecules or complexes in thebulk solid. Accordingly, polymorphs are distinct solids sharing the samemolecular formula yet having distinct advantageous physical propertiescompared to other crystalline forms of the same compound or complex.

All forms of erlotinib or a pharmaceutically acceptable salt thereof areintended to be within the scope of the present invention.

Although it is possible to administer the compound of the presentinvention in the form of a bulk active chemical, it is preferred toadminister the compound in the form of a pharmaceutical composition orformulation. Thus, one aspect the present invention includespharmaceutical compositions comprising erlotinib and/or pharmaceuticallyacceptable salts thereof and one or more pharmaceutically acceptablecarriers, diluents, or excipients.

The manner in which the compound of the present invention isadministered can vary. The compound of the present invention ispreferably administered orally. Preferred pharmaceutical compositionsfor oral administration include tablets, capsules, caplets, syrups,solutions, and suspensions. The pharmaceutical compositions of thepresent invention may be provided in modified release dosage forms suchas time-release tablet and capsule formulations.

The compounds of the present invention may be used in the treatment of avariety of disorders and conditions and, as such, may be used incombination with a variety of other suitable therapeutic agents usefulin the treatment or prophylaxis of those disorders or conditions.

As used herein, the terms “pharmaceutically acceptable composition” or“pharmaceutical composition” refer to erlotinib or a pharmaceuticallyacceptable salt thereof optionally admixed with one or morepharmaceutically acceptable carriers, diluents, or excipients.Pharmaceutically acceptable compositions preferably exhibit a degree ofstability to environmental conditions so as to make them suitable formanufacturing and commercialization purposes.

Pharmaceutically acceptable compositions may comprise a pharmaceuticallyacceptable carrier, adjuvant, or vehicle, which, as used herein,includes any and all solvents, diluents, or other liquid vehicle,dispersion or suspension aids, surface active agents, isotonic agents,thickening or emulsifying agents, preservatives, solid binders,lubricants and the like, as suited to the particular dosage formdesired. As an example, Remington's Pharmaceutical Sciences, SixteenthEdition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) disclosesvarious carriers used in formulating pharmaceutically acceptablecompositions and known techniques for the preparation thereof. Exceptinsofar as any conventional carrier medium is incompatible witherlotinib or a pharmaceutically acceptable salt thereof, such as byproducing any undesirable biological effect or otherwise interacting ina deleterious manner with any other component(s) of the pharmaceuticallyacceptable composition, its use is contemplated to be within the scopeof this invention. Some examples of materials which can serve aspharmaceutically acceptable carriers include, but are not limited to,ion exchangers, alumina, aluminum stearate, lecithin, serum proteins,such as human serum albumin, buffer substances such as phosphates,glycine, sorbic acid, or potassium sorbate, partial glyceride mixturesof saturated vegetable fatty acids, water, salts or electrolytes, suchas protamine sulfate, disodium hydrogen phosphate, potassium hydrogenphosphate, sodium chloride, zinc salts, colloidal silica, magnesiumtrisilicate, polyvinyl pyrrolidone, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, wool fat, sugars such aslactose, glucose and sucrose; starches such as corn starch and potatostarch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; powdered tragacanth;malt; gelatin; talc; excipients such as cocoa butter and suppositorywaxes; oils such as peanut oil, cottonseed oil; safflower oil; sesameoil; olive oil; corn oil and soybean oil; glycols; such a propyleneglycol or polyethylene glycol; esters such as ethyl oleate and ethyllaurate; agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

Pharmaceutically acceptable compositions can be administered to humansand other animals orally, rectally, parenterally, intracisternally,intravaginally, intraperitoneally, topically (as by powders, ointments,or drops), bucally, as an oral or nasal spray, or the like.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compound(s),a liquid dosage form may contain inert diluents commonly used in the artsuch as, for example, water or other solvents, solubilizing agents andemulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate,ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol,1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed,groundnut, corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid may be incorporated in an injectable product.The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the invention, it isoften desirable to slow the absorption of the compound from subcutaneousor intramuscular injection. This may be accomplished by the use of aliquid suspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the compound then depends upon itsrate of dissolution that, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered compound form is accomplished by dissolving or suspendingthe compound in an oil vehicle. Injectable depot forms are made byforming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or (a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, (b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, (c) humectants such as glycerol, (d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, (e) solutionretarding agents such as paraffin, (f) absorption accelerators such asquaternary ammonium compounds, (g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolinand bentonite clay, and (i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

Erlotinib or a pharmaceutically acceptable salt thereof may beformulated using nanotechnology. Nanoparticles are attractive formedical purposes based on their unique features, such as their surfaceto mass ratio being larger than that of other particles, their quantumproperties, and their ability to adsorb and carry other compounds.Nanoparticles may have dimensions below 0.1 μm or 100 nm. Alternatively,a pharmaceutical composition may comprise relatively large (size>100 nm)nanoparticles, as needed for loading a sufficient amount of drug ontothe particles. In addition, for drug delivery, not only engineeredparticles may be used as carrier, but also the drug itself may beformulated at a nanoscale, and then function as its own carrier. Thecomposition of the engineered nanoparticles may vary. Source materialsmay be of biological origin like phospholipids, lipids, lactic acid,dextran, chitosan, or have more chemical characteristics like variouspolymers, carbon, silica, and metals. Especially in the area ofengineered nanoparticles of polymer origin there is a vast area ofpossibilities for the chemical composition. See, for example, Martins etal., Nanoparticle Drug Delivery Systems: Recent Patents and Applicationsin Nanomedicine, Recent Patents on Nanomedicine, 2013, 3(2), pp. 1-14.Many cytotoxic chemotherapeutic agents have poor aqueous solubility.These molecules are associated with poor physicochemical andbiopharmaceutical properties, which makes the formulation difficult. Oneapproach in this regard is the use of combination of cyclodextrin andnanotechnology in delivery system. See, for example, Gidwani et al., AComprehensive Review on Cyclodextrin-Based Carriers for Delivery ofChemotherapeutic Cytotoxic Anticancer Drugs, BioMed ResearchInternational, Volume 2015, Article ID 198268, 15 pages. Cyclodextrinsare chemically and physically stable macromolecules produced byenzymatic degradation of starch. They are water-soluble, biocompatiblein nature with hydrophilic outer surface and lipophilic cavity. Theyhave the shape of truncated cone or torus rather than perfect cylinderbecause of the chair conformation of glucopyranose unit. Cyclodextrinsare classified as natural and derived cyclodextrins. Naturalcyclodextrins comprise three well-known industrially produced (major andminor) cyclic oligosaccharides. The most common natural cyclodextrinsare α, β, and γ consisting of 6, 7, and 8 glucopyranose units. They arecrystalline, homogeneous, and nonhygroscopic substances. Amongst these,β-cyclodextrin is used for complexation due to perfect cavity size,efficient drug complexation and loading, availability, and relativelylow cost. Various hydrophilic, hydrophobic, and ionic derivatives havebeen developed and utilized to improve the physicochemical andbiopharmaceutical properties of drug and inclusion capacity of naturalcyclodextrins. Hydroxypropyl-β-cyclodextrin (HP-β-CD), randomlymethylated-β-cyclodextrin (RM-β-CD), and sulfobutylether-β-cyclodextrin(SBE-β-CD) are mostly preferred for complexation. Polymerizedcyclodextrins are high molecular weight compounds, either water-solubleor insoluble. They offer the advantage of amorphous state andcomplexation without toxic effects. Examples of polymerizedcyclodextrins are soluble anionic β-cyclodextrin polymer, solubleγ-cyclodextrin polymer, and epichlorohydrin β-cyclodextrin polymer.Cyclodextrin-based nanocarriers may be prepared by utilizing the conceptof dual approach, which involves combination of two different approachesin a single delivery system. This covers two aspects firstly; theanticancer drug is complexed with suitable cyclodextrin and secondlyencapsulation of complexed drug into carrier.

Erlotinib or a pharmaceutically acceptable salt thereof may also be inmicroencapsulated form with one or more excipients as noted above. Thesolid dosage forms of tablets, dragees, capsules, pills, and granulescan be prepared with coatings and shells such as enteric coatings,release controlling coatings and other coatings well known in thepharmaceutical formulating art. In such solid dosage forms the activecompound may be admixed with at least one inert diluent such as sucrose,lactose or starch. Such dosage forms may also comprise, as is normalpractice, additional substances other than inert diluents, e.g.,tableting lubricants and other tableting aids such a magnesium stearateand microcrystalline cellulose. In the case of capsules, tablets andpills, the dosage forms may also comprise buffering agents. They mayoptionally contain opacifying agents and can also be of a compositionthat they release the active ingredient(s) only, or preferentially, in acertain part of the intestinal tract, optionally, in a delayed manner.Examples of embedding compositions that can be used include polymericsubstances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, the inventioncontemplates the use of transdermal patches, which have the addedadvantage of providing controlled delivery of a compound to the body.Such dosage forms are prepared by dissolving or dispensing the compoundin the proper medium. Absorption enhancers can also be used to increasethe flux of the compound across the skin. The rate can be controlled byeither providing a rate controlling membrane or by dispersing thecompound in a polymer matrix or gel.

The compounds of this invention may be made by a variety of methods,including well-established synthetic methods. Illustrative generalsynthetic methods are set out below and then specific compounds of theinvention are prepared in the working Examples. The compounds can beprepared according to the methods described below using readilyavailable starting materials and reagents. In these reactions, variantsmay be employed which are themselves known to those of ordinary skill inthis art but are not described in detail here.

Reference is made to U.S. RE 41,065 and incorporated herein by referencewith regard to the description and synthesis of TARCEVA® (erlotinibhydrochloride).

EXAMPLES Specific Example 1: Pulse-Continuous Erlotinib Results inImpressive Control of Central Nervous System Disease

Based on evolutionary mathematical modeling data, the present inventorstested a novel schedule of twice weekly pulse erlotinib in combinationwith daily erlotinib as initial EGFR TKI treatment in patients withEGFR-mutant lung cancers.

The trial was a prospective, open-label, single center phase 1dose-escalation study of twice weekly pulse dose and daily erlotinib inpatients with EGFR-mutant lung cancers. The primary endpoint of thestudy was the identification of the maximum tolerated dose of thecombination of twice weekly high dose and daily low dose erlotinib.Secondary endpoints included the measurement of progression-freesurvival, overall survival, complete and partial response rate,determination of central nervous system progression and pharmacokineticanalysis. The study was registered at clinicaltrials.gov (NCT01967095).The trial was conducted after approval from the institutional reviewboard at Memorial Sloan Kettering. All patients provided writteninformed consent.

Patients had stage IV or recurrent EGFR-mutant lung adenocarcinomas andno prior treatment with an EGFR TKI. Prior cytotoxic chemotherapy wasallowed. Patients were required to have measurable disease per RECIST(Response Evaluation Criteria in Solid Tumours), version 1.1). Patientsmust have had adequate organ function and a Karnofsky performance statusof >70%, with reference to Karnofsky et al., The Use of the NitrogenMustards in the Palliative Treatment of Carcinoma-with ParticularReference to Bronchogenic Carcinoma, Cancer, 1948; 1(4):634-56. Patientswith clinically stable brain metastases, either treated or untreated,were eligible.

Study Design

The study used a standard 3+3 dose escalation design. Three patientswere enrolled at each dose level and assessed for 1 full cycle before adose escalation decision was made. No intra-patient dose escalation wasallowed. Cycle 1, week 1 (Days 1-7) consisted of pulse dose erlotinib ondays 1 and 2 without daily low dose erlotinib on days 3 to 7. For allsubsequent weeks, patients received pulse dose erlotinib on days 1 and2, and erlotinib 50 mg oral daily for 5 days on days 3 to 7 which wasrepeated weekly to complete 21 day cycles. Cycle 1 was 4 weeks toaccount for one week of lead in pulse dose erlotinib only. For each doselevel, the dose of pulse erlotinib on days 1-2 was escalated(supplemental Table 1).

Supplemental Table 1: Dose levels and the number of patients treated andany DLTs observed in the first cycle:

Number treated DLT Dose level 1: 600 mg 3 None pulse Dose level 2: 750mg 3 None pulse Dose level 3: 900 mg 3 None pulse Dose level 4: 1050 mg6 1 (grade 3 ALT/AST) pulse Dose level 5: 1200 mg 6 None pulse (+10 inexpansion) Dose level 6: 1350 mg 3 2 (grade 2 rash, grade 3 pulsemucositis)

Patients who did not experience a dose-limiting toxicity (DLT) continuedtreatment at the assigned dose until progression of disease,unacceptable toxicity, or withdrawal of informed consent. Dosereductions of the pulse dose were allowed for toxicity, in 150 mgincrements.

Toxicity assessments: Patients were assessed five times during cycle 1(28 days) and then every 21 days thereafter. Patient history, physicalexamination, complete blood count and serum chemistries were performedat each visit. Toxicity was graded according to the National CancerInstitute Common Terminology Criteria for Adverse Events (NCI CTCAE),version 4. Dose-limiting toxicity was defined as any grade 4 hematologictoxicity lasting greater than 5 days. Grade 3 thrombocytopenia withclinically significant bleeding was considered a DLT. All grade 3 orgreater non-hematologic toxicities were considered DLTs with diarrhea,nausea and vomiting needing to be grade 3 for 72 hours despite maximalsupportive care to qualify as a DLT. Once the maximum tolerated dose(MTD) was determined, an additional ten patients were enrolled at theMTD.

Response assessments: Response to therapy was assessed by intervalimaging every 6 weeks with a CT scan with response evaluated per RECIST1.1. After six cycles on treatment, patients could reduce theradiographic assessments to every 4 cycles (12 weeks).

Pharmacokinetic analysis: Whole-blood samples for plasma were collectedat prescheduled time points for pharmacokinetic (PK) analysis. Plasmalevels of erlotinib were determined using a validated liquidchromatography-tandem mass spectrometry assay. LC-MS/MS was performedusing a Phenomenex Kinetex 2.6 μm core-shell Biphenyl column (50×3 mm)and Shimadzu HPLC. MS detection was using an AB SCI EX API 4000 triplequadrupole mass spectrometer operating in positive ion electrosprayionization (ESI) mode. Standard PK parameters were calculated using anoncompartmental method (WNNonlin, Pharsight).

Statistical Analysis: Descriptive statistics were used to summarize theclinical characteristics of the patients. Progression-free survival wasestimated using the Kaplan-Meier method, and defined as the time fromstart of study therapy until progression or death. Patients who did notexperience the event of interest were censored at the date they came offstudy or date of last assessment if still receiving study therapy.Response rates were calculated using binomial proportions and exact 95%Cls. All statistical analyses were performed using R 3.2.2 (RDevelopment Core Team) including the “survival” and “Hmisc” packages.

Results

34 patients were enrolled onto this study, including 24 patients on thedose escalation portion of the phase 1 study and 10 patients in anexpansion cohort at the MTD. In total, sixteen patients were treated atthe MTD. The clinical characteristics of all patients are listed inTable 1.

TABLE 1 Patient characteristics Patient Characteristics Age, Median(range) 61 (33-77) Sex Female 18 Male 16 KPS (%) 90-100 16 80 15 70 3Smoking status Former (pack-yr range) 12 (<1-35) Never 22 EGFRsensitizing mutation L858R 12 Exon 19 deletion 21 G719A 1 Prior therapyYes 5 No 29 CNS involvement at diagnosis Yes 11 Treated 5 WBRT 3 SRS 1Craniotomy 1 Untreated 6 No 22

Eleven patients (32%) had brain metastases at diagnosis, 5 of whomreceived treatment (surgery or radiation) for their CNS disease prior tostudy enrollment.

Determination of the maximum tolerated dose: There were no DLTs seen atdose levels at the 600, 750 and 900 mg pulse dose levels. At theerlotinib 1050 mg pulse dose, there was one DLT of grade 3 transaminitis(Supplemental Table 1, above).

At 1350 mg pulse dose level, there were two DLTs: grade 3 rash and grade3 mucositis. We then enrolled an additional three patients on to the1200 mg erlotinib pulse dose level with no DLTs seen. The 1200 mg pulseon days 1 and 2 and 50 mg erlotinib on days 3 to 7 was determined to bethe MTD.

Adverse events: All 34 patients were evaluable for toxicity (Table 2).No grade four or five toxicities were reported with no deaths on study.Most drug-related toxicities were grade 1 and 2. The most common (>25%)drug-related adverse events were rash, diarrhea, nausea, fatigue,mucositis, pruritus, vomiting, increased bilirubin and dry skin (Table2). Of the sixteen patients treated at the MTD, only three of sixteenrequired a dose reduction of the pulse dose erlotinib; the reasons fordose reduction were grade 3 rash, intolerable grade 2 rash andintolerable grade 2 diarrhea. All three patients eventually were loweredto erlotinib 900 mg as the pulse dose. Six patients were removed fromthe study for toxicity: hyperbilirubinemia (1), possible pneumonitis(1), diarrhea (2), transaminitis (1) and mucositis (1).

TABLE 2 Study drug-related adverse events seen in ≥10% of patientsAdverse Event Grade 1 Grade 2 Grade 3 Grade 4 Total (any grade) Rash 21(62%) 8 (24%) 1 (3%) 0 30 (88%) Diarrhea 24 (71%) 1 (3%) 4 (12%) 0 29(85%) Nausea 10 (29%) 3 (9%) 2 (6%) 0 15 (44%) Fatigue 8 (24%) 4 (12%) 00 12 (35%) Mucositis 8 (24%) 3 (9%) 1 (3%) 0 12 (35%) Pruritis 11 (32%)0 0 0 11 (32%) Vomiting 9 (26%) 1 (3%) 1 (3%) 0 11 (32%) Bilirubinincreased 4 (12%) 5 (15%) 2 (6%) 0 11 (32%) Dry skin 10 (29%) 0 0 0 10(29%) ALT elevated 6 (18%) 1 (3%) 1 (3%) 0 8 (24%) Alopecia 7 (21%) 0 00 7 (21%) AST increased 5 (15%) 1 (3%) 0 0 6 (18%) Paronychia 4 (12%) 2(6%) 0 0 6 (18%) Anorexia 3 (9%) 2 (6%) 0 0 5 (15%) Anemia 2 (6%) 1 (3%)1 (3%) 0 4 (12%)

Efficacy: All 34 patients were evaluable for response. Four patientscame off study prior to the first follow-up radiographic assessment (3due to toxicity, 1 due to noncompliance) and were counted asnon-responders in our intent to treat analysis. Twenty-four patients hadconfirmed partial responses and one patient had a complete response(FIG. 2). The overall response rate was 74% (95% Cl: 60-84%). Allpatients had a decrease in the sum of their target lesions. The maximumradiographic tumor change of target lesions for each patient with afollow up radiographic assessment is depicted in FIG. 2. The medianprogression-free survival is 9.9 months (95% Cl 5.8-15.4 months) (FIG.3). The overall survival estimate is not yet mature. Six subjects havedied: four due to lung cancer progression, one due to Parkinson'sdisease and one due to a second primary gastric cancer.

Central nervous system activity: A brain MRI was required at enrollment.Eleven patients (32%) had brain metastases at study entry. No patienthad leptomeningeal disease. Prior to the trial, 3 patients had wholebrain radiation, 1 had stereotactic radiosurgery and 1 had a surgicalresection. All 6 patients with untreated brain metastases had evidenceof tumor regression in the CNS (FIG. 4). No patients had clinical CNSprogression on study treatment. Of the 19 patients who came off studyfor progression of disease, 16 had CNS imaging within three months ofcoming off study and none had radiographic evidence of new orprogressing brain metastases.

TABLE 3 Molecular findings at diagnosis and at acquired resistance forpatients who came off study for progression Baseline Acquired Resistance(off study for progression) Pt EGFR Concurrent mutations EGFR T790MConcurrent mutations 1 Ex19 del Not done Ex19 del Positive Not done 2Ex19 del Not done Ex19 del Positive AURKA amp, GNAS amp, MEF2B gain,CCNE1 gain, AKT2 gain, MCL1 gain 3 Ex19 del Not done Ex19 del NegativeCDK2NB del, CDKN2A del, BAP1 G109V, ETV1 R163Q, NOTCH3 G1689A 4 Ex19 delNot done Ex19 del Positive Not done 5 Ex19 del Not done Ex19 delPositive CCND2 amp, VEGFA amp, TERT gain, MDC1 gain, CDKN2B del, CDKN2Adel, PAX5 del, AKT3 R166*, CSF1R A74T, INSR D1259A 6 L858R Not doneL858R Negative Not done 7 L858R Not done L858R Failed Failed 8 L858R Notdone L858R Positive TP53 M246V, APC S1100fs, BRIP1 I983fs, FBXW7 C573Y,RUNX1 ex5 del 9 Ex19 del Not done Ex19 del Positive Not done 10 Ex19 delNot done Ex19 del Positive Not done 11 Ex19 del TP53 E298X, EGFR Ex19del Positive TP53 E298X, EGFR amp, amp, MYC amp, ERBB2 amp, RAD21 amp,RECQL4 amp, RB1 MYC amp, SDHA amp, TERT del, PDGFR R804Q, amp, IL7R amp,RICTOR SETD2 N16343fs amp, RECQL4 amp, RB1 del, PDGFR R804Q, SETD2 12Ex19 del TP53 Q104X, EGFR Ex19 del Positive Failed amp, MYC amp, FLT1R1146T, MCL1 G3S, PTPRD S569L 13 Ex19 del Not done Ex19 del PositiveFailed 14 L858R EGFR V689F, FGFR3 L858R Negative EGFR V689F, FGFR3R399C, R399C, TP53 P36fs, TP53 P36fs, AR G578X, AR G578X, ATRX ATRXS784F, BARD1 N73S, S784F, BARD1 N73S, EPHA3 F152S, RET E164K EPHA3F152S, SMARCA4 P1277L 15 Ex19 del Not done Ex19 del Positive EGFR L747P,TP53 Y163N, PTEN F271S 16 Ex19 del GNA11 R210L, TP53 Ex19 del PositiveGNA11 R210L, TP53 C275W, PMS2 amp, C275W, NKX2-1 amp, RAC1 amp, EGFRFOXA1 amp, CENPA E50fs, amp, NKX2-1 amp, PLCG2 P999T, RB1 ex10 FOXA1amp, SV, STAG2 D26E, TET1 PTEN del, GNAS Q683P K25N, RB1 ex10 SV, STAG2D26E, TET1 17 Ex19 del Not done Ex19 del Positive PIK3CA E542K, TP53V73fs, CCNE1 amp, EGFR amp, RICTOR gain, IL7R I121fs, MAP2K4 R304*, MLL3D3461N 18 Ex19 del Not done Ex19 del Positive PIK3CA E542K, CTNNB1 S33F,LATS1 K652R, TGFBR2 K399fs 19 Ex19 del PIK3CA E545K, Ex19 del NegativePIK3CA E545K, TP53 ex5 TP53 ex5 del, del, MET gain, EGFR gain, EGFRgain, SETD2 T2316A EPHB1 E144K, Amp = amplification, del = deletion

Mechanisms of acquired resistance: Of the nineteen patients thatprogressed on study therapy, six continued daily erlotinib at standarddoses for >2 months after discontinuation of study therapy. Nineteenpatients had a tumor biopsy at the time of progression. One patient'sbiopsy sample was inadequate for molecular analysis. Fourteen ofeighteen (78%, 95% Cl 54%-91%) patients had EGFR T790M identified intheir rebiopsy specimen. Of the eighteen patients, eleven patients hadnext generation sequencing of their acquired resistance biopsy sample,and four had a paired pre-treatment tumor sample as well. Multipleconcurrent mutations were found in both baseline and acquired resistancetumor samples in addition to the sensitizing EGFR mutation which wasidentified in all samples. Acquired molecular alterations not present inbaseline samples included HER2 and MET amplification which have beenpreviously reported (33, 34) as well as amplification in RAD21, SDHA,TERT, IL7R and RICTOR, and mutations in RET E164K, CENPA E50fs, andPLCG2 P999T.

Pharmacokinetic analysis: Samples were collected from all 34 patients inthe phase 1 study at the pre-specified time points. Median plasmaconcentration-time profiles are shown in FIG. 5. There was significantintra-patient variability in erlotinib plasma concentrations. Nosignificant increase in peak plasma concentration was observed withincreasing pulse doses of erlotinib from 600 mg to 1,350 mg, at any timepoint examined during Cycle 1. This was also confirmed by analysis ofthe major erlotinib drug metabolites (OSI-420 and M11), which showed nosignificant dose-dependence with increasing pulse doses of erlotinib.The peak plasma concentration occurred after the second day of weeklypulse dose at Week 2, with median plasma concentration at 4 hrpost-administration reaching 5,393 ng/mL (range 2,600-9355 ng/mL),approximately 13.7 micromolar, more than 5 times the peak plasmaconcentration seen with standard 150 mg dosing (35). The median plasmatrough concentration before the pulse dosing at the start of week 4 was435 ng/mL (range: 29-1655 ng/mL), a concentration of 1.1 micromolar.This level at week 4 is consistent with 24 hr plasma concentrationsobserved following standard 150 mg dosing (35).

Patient disposition: six patients remain enrolled in the study. Nineteenpatients discontinued study therapy because of progressive disease, andsix others for adverse events discussed above. Two patients stoppedstudy therapy due to non-compliance and one due to the development of anunrelated gastric adenocarcinoma.

We believe this is the first time evolutionary cancer modeling was usedto optimize dosing of a targeted therapy. This dosing schedule derivedfrom mathematical modeling did not delay the development of resistanceor prevent the emergence of EGFR T790M despite validation in vitro andin vivo pre-clinical models. A likely explanation is that the peakplasma concentrations in patients may not have been high enough tocorrespond to the peak concentrations utilized in the pre-clinicalmodels. The pulse and low dose concentrations used in the pre-clinicalmodels were 20 micromolar and 1 micromolar, respectively. The medianpeak and trough concentration obtained at the MTD in our study was 13.7micromolar and 1.1 micromolar, respectively. We were limited inexploring higher pulse dose levels due by toxicity resulting in DLTs. Inaddition, in the relatively few samples obtained in this phase 1 study(n=3-6 for dose levels 1-4 and 6), there were no significant increasesin plasma peak concentration with increasing pulse doses from 600 mg to1,350 mg, presumably due to limitations in drug absorption or due todrug clearance or metabolism. Even if toxicity were not an issue athigher dose levels, it is uncertain whether shorter dosing intervals orhigher doses would result in the peak plasma concentrations required todelay EGFR T790M. The peak concentrations of erlotinib required to delayEGFR T790M do not appear achievable clinically. There are otherpotential limitations to our clinical model that may have contributed toour negative findings. The original modeling utilized both pulseafatinib and erlotinib, with the combination of pulse afatinib and dailyerlotinib as superior at delaying resistance. Differences betweenerlotinib and afatinib may translate to disparate activity against EGFRT790M, and our results may have been different if we had utilized pulseafatinib. In addition, there are limitations inherent to any modelsystem that considers multiple variables but cannot fully account forthe entire complexity of all host and tumor factors.

Pulse-continuous erlotinib was well tolerated. The most common treatmentrelated adverse events were rash, diarrhea, nausea, fatigue andmucositis. When compared to prospective studies of standard daily dosederlotinib and afatinib, BR.21 and Lux-Lung 3, respectively, toxicity wassimilar. See, Sequist et al., Phase III Study of Afatinib or CisplatinPlus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma WithEGFR Mutations, Journal of Clinical Oncology, 2013, 31(27):3327-34, andShepherd et al., Erlotinib in previously treated non-small-cell lungcancer, The New England Journal of Medicine, 2005, 353(2):123-32.

Surprisingly, the study showed no significant increase in toxicity withpulse continuous erlotinib, despite a five times increase in the medianpeak plasma concentration of erlotinib compared to standard dosing. See,Hamilton et al., Effects of smoking on the pharmacokinetics oferlotinib, Clinical Cancer Research, 2006, 12(7 Pt 1):2166-71. Pulsedosing may result in decreased toxicity compared to the same amount ofdrug divided among daily doses, as toxicity may be related to drugtrough or steady state concentrations, rather than peak concentrations.

This observation is corroborated by our previous study of once weeklypulse dose erlotinib at 2000 mg once weekly which also showed a similartoxicity profile to standard daily dose erlotinib. See, Milton et al., Aphase I/II study of weekly high-dose erlotinib in previously treatedpatients with nonsmall cell lung cancer, Cancer, 2006, 107(5):1034-41.The present study demonstrates that pulse-continuous erlotinib is afeasible dosing schedule that is tolerated by most people.

The efficacy of pulse continuous erlotinib was similar to standard doseerlotinib for lung cancer. The overall response rate was 74% (95% Cl60-84%) and the median progression free survival was 9.9 months (95% Cl5.8-15.4 months). The dose and schedule of erlotinib assessed in thisclinical trial did not improve response rates, prolong progression freesurvival or delay systemic resistance. The 78% (95% Cl 54%-91%)frequency of EGFR T790M at the time of acquired resistance wascomparable what is seen with standard dosing. Further study is needed toinvestigate whether drug dosing alters the mechanisms of resistance thatemerge. Central nervous system metastases are a critical issue in themanagement of patients with EGFR-mutant lung cancers. Due to a prolongeddisease course and improved overall survival, EGFR-mutant cancers may beenriched for CNS involvement with the cumulative incidence of CNSmetastases approaching 60%. See, for example, Heon et al., The impact ofinitial gefitinib or erlotinib versus chemotherapy on central nervoussystem progression in advanced non-small cell lung cancer with EGFRmutations, Clinical Cancer Research, 2012, 18(16):4406-14; Omuro et al.,High incidence of disease recurrence in the brain and leptomeninges inpatients with nonsmall cell lung carcinoma after response to gefitinib,Cancer, 2005, 103(11):2344-8; Lee et al., Frequent central nervoussystem failure after clinical benefit with epidermal growth factorreceptor tyrosine kinase inhibitors in Korean patients withnonsmall-cell lung cancer, Cancer, 2010, 116(5):1336-43; Heon et al.,Development of central nervous system metastases in patients withadvanced non-small cell lung cancer and somatic EGFR mutations treatedwith gefitinib or erlotinib, Clinical Cancer Research, 2010,16(23):5873-82; Rangachari et al., Brain metastases in patients withEGFR-mutated or ALK-rearranged non-small-cell lung cancers, Lung Cancer,2015, 88(1):108-11; and Kris et al., Using Multiplexed Assays ofOncogenic Drivers in Lung Cancers to Select Targeted Drugs, J. Am. Med.Assoc., 2014; 311(19):1998-2006.

Despite new treatments, such as osimertinib, that have demonstratedimpressive systemic efficacy, CNS failures on treatment are common. Inaddition, patients with CNS involvement demonstrate lower response rateand shorter progression free survival with the 3rd generation EGFR TKIscompared to patients without CNS metastases. See, Camidge et al.,Activity of Rociletinib in EGFR Mutant NSCLC Patients With a History ofCNS Involvement World Conference on Lung Cancer, 2015, Oral presentationat the World Conference on Lung Cancer, Denver, Colo.

This is believed to be the first demonstration of pre-treatmentincidence of CNS involvement in study subjects and also the rate of CNSprogression on an EGFR TKI therapy. None of the prior large prospectivestudies of EGFR tyrosine kinase inhibitors include this information.See, for example, Rosell et al., Erlotinib versus standard chemotherapyas first-line treatment for European patients with advanced EGFRmutation-positive non-small-cell lung cancer (EURTAC): a multicentre,open-label, randomised phase 3trial, The Lancet Oncology, 2012,13(3):239-46; Sequist et al., Phase III Study of Afatinib or CisplatinPlus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma WithEGFR Mutations, Journal of Clinical Oncology, 2013, 31(27):3327-34;Janne et al., Randomized Phase II Trial of Erlotinib Alone or WithCarboplatin and Paclitaxel in Patients Who Were Never or Light FormerSmokers With Advanced Lung Adenocarcinoma: CALGB 30406 Trial, Journal ofClinical Oncology, 2012, 39(17): 2063-9; Zhou et al., Erlotinib versuschemotherapy as first-line treatment for patients with advanced EGFRmutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): amulticentre, open-label, randomised, phase 3 study, The Lancet Oncology,2011, 12(8):735-42; and Mitsudomi et al., Gefitinib versus cisplatinplus docetaxel in patients with non-small-cell lung cancer harbouringmutations of the epidermal growth factor receptor (WJTOG3405): an openlabel, randomised phase 3 trial, The Lancet Oncology, 2010, 11(2):121-8.

As site of failure has prognostic as well as treatment implications, thepresent inventors suggest the rate of CNS failure be explicitly reportedin all future prospective studies in lung cancers. Within EGFR-mutantlung cancers, understanding the CNS efficacy of drugs is criticallyimportant and will help in the selection between and among drugs thatmay have similar systemic effect.

The pulse continuous erlotinib dosing resulted in response inpre-existing brain metastases and prevention of new brain metastaseswhile on treatment. Using retrospective data, CNS progression with orwithout concurrent systemic progression can occur in up to 33% ofpatients treated with standard dosing of EGFR TKI, with isolated CNSprogression in up to 19% of cases. Heon et al., The impact of initialgefitinib or erlotinib versus chemotherapy on central nervous systemprogression in advanced non-small cell lung cancer with EGFR mutations,Clinical Cancer Research, 2012, 18(16):4406-14; Omuro et al., Highincidence of disease recurrence in the brain and leptomeninges inpatients with nonsmall cell lung carcinoma after response to gefitinib,Cancer, 2005, 103(11):2344-8; and Lee et al., Frequent central nervoussystem failure after clinical benefit with epidermal growth factorreceptor tyrosine kinase inhibitors in Korean patients withnonsmall-cell lung cancer, Cancer, 2010, 116(5):1336-43.

The present data suggests that the CNS efficacy of this dosing schedulemay be superior. The pulse continuous dosing allows for increased CNSpenetration but continued daily dosing maintains systemic control ofdisease.

In summary, this is the first prospective study to assess an alternativedosing of an approved tyrosine kinase inhibitor based on evolutionarymodeling. The regimen was well tolerated with a similar toxicity profileto standard dose erlotinib. Pulse continuous erlotinib did not lengthenprogression-free survival or prevent the emergence of EGFR T790M as washypothesized, perhaps due to the inability to achieve high enough plasmaconcentrations with the pulse doses used in this study. Surprisingly,however, none of the patients on study had evidence of new orprogressing CNS disease on this regimen.

Specific Example 2: Adjuvant Therapy

Adjuvant therapy or care, also called adjunct therapy or adjunctivetherapy or care, is therapy that is given in addition to the primary,main, or initial therapy to maximize its effectiveness. As an adjuvantagent modifies the effect of another agent, so adjuvant therapy modifiesother therapy.

For example, resectable non-small-cell lung cancer (NSCLC) accounts for20% to 25% of lung cancer cases diagnosed annually; however, only 60% ofpatients survive 5 years after surgery. The first trial to demonstrate asignificant survival benefit with adjuvant cisplatin-based chemotherapywas reported a decade ago. Subsequently, additional randomized trialsconfirmed the role of adjuvant chemotherapy in patients with pathologicstage II and III NSCLC, and subset analyses suggested a benefit inpatients with large IB tumors. A meta-analysis provided further supportfor adjuvant chemotherapy. Kelly et al., Adjuvant Erlotinib VersusPlacebo in Patients With Stage IB-IIIA Non-Small-Cell Lung Cancer(RADIANT): A Randomized, Double-Blind, Phase III Trial, Journal ofClinical Oncology, Published Ahead of Print on Aug. 31, 2015 as10.1200/JCO.2015.61.8918, sets forth a study design, patient population,assignment and masking protocol, study assessment, outcomes, andstatistical analysis that could be used for a study of adjuvantefficacy. As such, that reference is incorporated herein in its entiretyfor such purpose. As set forth in Kelly et al., id, the signal ofactivity observed with erlotinib in patients with EGFR-expressing tumorscombined with its oral availability and mild nonhematologic toxicityprofile led to its evaluation in earlier stages of lung cancer. TheRandomized Double-Blind Trial in Adjuvant NSCLC Wth Tarceva (RADIANT)study evaluated whether erlotinib would increase disease-free survival(DFS) in patients with completely resected stage IB to IIIA NSCLC whosetumors express EGFR.

As a further reference for conducting an adjuvant trial, Pennell et al.,SELECT: A Multicenter Phase II Trial of Adjuvant Erlotinib in ResectedEarly-stage EGFR Mutation-positive NSCLC, presented at the 2014 ASCOmeeting, provides study design, statistical considerations, patientcharacteristics, disease characteristics, treatment durations, dosemonitoring, and outcomes and is hereby incorporated by reference in itsentirety for such purpose.

The specific pharmacological responses observed may vary according toand depending on the particular active compound selected or whetherthere are present pharmaceutical carriers, as well as the type offormulation and mode of administration employed, and such expectedvariations or differences in the results are contemplated in accordancewith practice of the present invention.

Although specific embodiments of the present invention are hereinillustrated and described in detail, the invention is not limitedthereto. The above detailed descriptions are provided as exemplary ofthe present invention and should not be construed as constituting anylimitation of the invention. Modifications will be obvious to thoseskilled in the art, and all modifications that do not depart from thespirit of the invention are intended to be included with the scope ofthe appended claims.

What is claimed is:
 1. A method for controlling formation ofleptomeninges lesions in a patient with non-small cell lung cancer(NSCLC) that harbors an epidermal growth factor receptor (EGFR) mutationwith pre-existing leptomeningeal metastases, the method comprising: a.orally administering to the patient one or more pulse dose of erlotinibor a pharmaceutically acceptable salt thereof, wherein the pulse dose isbetween 1200 mg to about 1350 mg of erlotinib or a pharmaceuticallyacceptable salt thereof, wherein the one or more pulse dose of erlotinibor a pharmaceutically acceptable salt thereof is administered twiceweekly; and b. orally administering to the patient one or more dailydose of erlotinib or a pharmaceutically acceptable salt thereof, whereinthe daily dose is from about 25 mg to about 50 mg of erlotinib or apharmaceutically acceptable salt thereof, wherein after theadministering in a. and b. the patient exhibits a delay in one or moreof an unobservable increase in size of leptomeninges lesions, anunobservable new leptomeninges lesion; or a delay or decrease inleptomeningeal seeding in the cerebrospinal fluid (CSF), therebycontrolling the formation of leptomeninges lesions in a patient withnon-small cell lung cancer (NSCLC) that harbors an epidermal growthfactor receptor (EGFR) mutation with pre-existing leptomeningealmetastases.
 2. The method of claim 1, wherein the pulse dose isadministered once daily on each of days 1 and 2 of a weekly dosingschedule.
 3. The method of claim 1, wherein the daily dose isadministered once daily on each of days 3 to 7 of a weekly dosingschedule.
 4. The method of claim 1, wherein the pulse dose is 1200 mg oferlotinib or a pharmaceutically acceptable salt thereof.
 5. The methodof claim 1, wherein the daily dose is 50 mg of erlotinib or apharmaceutically acceptable salt thereof.
 6. The method of claim 1,wherein the patient experiences no tumor formation in the centralnervous system.
 7. The method of claim 1, wherein the patient'scerebrospinal fluid is cleared of malignant cells.
 8. The method ofclaim 1, wherein the patient achieves an objective or complete responseor disease control.
 9. The method of claim 8, wherein the control isdurable.
 10. A method for controlling formation of malignant cells inthe cerebrospinal fluid (CSF) in a patient with non-small cell lungcancer (NSCLC) that harbors an epidermal growth factor receptor (EGFR)mutation with pre-existing CSF metastases, the method comprising: a.orally administering to the patient one or more pulse dose of erlotinibor a pharmaceutically acceptable salt thereof, wherein the pulse dose isbetween 1200 mg to about 1350 mg of erlotinib or a pharmaceuticallyacceptable salt thereof, wherein the one or more pulse dose of erlotinibor a pharmaceutically acceptable salt thereof is administered twiceweekly; and b. orally administering to the patient one or more dailydose of erlotinib or a pharmaceutically acceptable salt thereof, whereinthe daily dose is from about 25 mg to about 50 mg of erlotinib or apharmaceutically acceptable salt thereof, wherein after theadministering in a. and b., the patient exhibits clearing of malignantcells from the CSF, thereby controlling the formation of malignant cellsin the cerebrospinal fluid in a patient with non-small cell lung cancer(NSCLC) that harbors an epidermal growth factor receptor (EGFR) mutationwith pre-existing CSF metastases.
 11. The method of claim 10, whereinthe pulse dose is administered once daily on each of days 1 and 2 of aweekly dosing schedule.
 12. The method of claim 10, wherein the dailydose is administered once daily on each of days 3 to 7 of a weeklydosing schedule.
 13. The method of claim 10, wherein the pulse dose is1200 mg of erlotinib or a pharmaceutically acceptable salt thereof. 14.The method of claim 10, wherein the daily dose is 50 mg of erlotinib ora pharmaceutically acceptable salt thereof.
 15. The method of claim 10,wherein the patient experiences no tumor formation in the centralnervous system.
 16. The method of claim 10, wherein the patient achievesan objective or complete response or disease control.
 17. The method ofclaim 16, wherein the control is durable.
 18. The method of claim 1,wherein the patient does not experience grade 4 or grade 5 toxicity. 19.The method of claim 1, wherein the patient experiences grade 1 or grade2 toxicity.
 20. The method of claim 10, wherein the patient does notexperience grade 4 or grade 5 toxicity.
 21. The method of claim 10,wherein the patient experiences grade 1 or grade 2 toxicity.